Targeting hepatic CREB to reduce glucose output as a treatment option for diabetes is a highly controversial notion. Inhibition of CREB activity in the liver using a dominant-negative approach caused increased hepatic triglyceride content, suggesting that CREB is a poor target. In contrast, a recent report using antisense oligonucleotides (ASO) suggested that CREB inhibition prevented hepatic steatosis and insulin resistance However, given the systemic application of the ASO, and the repression of CREB in other metabolic tissues such as adipose tissue, this report did not directly address the function of CREB in the liver. During the past grant cycle, we have completed a systematic, genome-wide evaluation of CREB binding in the mammalian liver using ChlP-Seq analysis. Strikingly, four genes central to circadian regulation are direct CREB targets, suggesting a novel role for CREB in the maintenance of the peripheral clock in the liver. This is relevant, because night-shift work and other disruptions of circadian rhythms increase the risk of metabolic syndrome, including obesity, insulin resistance, and dyslipidemia in humans. Based on the above, we propose three specific aims. In AIM 1, we will determine if CREB ablation in hepatocytes can be used to alleviate hepatic insulin resistance and steatosis. We have derived two new models that will enable us to analyze CREB function in a precise, cell-type specific manner, a conditional null allele for CREB (CREB[loxp), and a conditional CREB Ser133 to Ala133 mutation (CREB][loxp](S133A)). These two alleles allow us to dissociate the contribution of CREB phosphorylation by protein kinase A versus all CREB functions. In AIM 2, we will determine the contribution of CREB to the control of the peripheral clock in the liver. Mice will also be subjected to restricted feeding to study the contribution of CREB to shifting part of the liver's circadian clock in this paradigm. In AIM 3, we will determine the role of CREB in nutritional control of the neuroendocrine axis. We will ablate CREB in the hypothalamus to assess its contribution to the regulation of TRH, and its role in feeding-dependent thermogenesis.